tbuckley/cabot-search huggingface dataset:
Abstract P1105: Inflammatory Bowel Disease Induced Autonomic Dysregulation Increases The Risk For Atrial Fibrillation
Authors: Andres F Pelaez, Disha Varma, Carlos H Pereira, Jonathas F Almeida, Jeremiah Wasserlauf, Ali Keshavarzian, Kathrin Banach
Journal: Circulation Research (2022)

Introduction: Ulcerative colitis causes inflammation of the innermost lining of the colon and rectum. The disease has a relapsing and remitting course and is accompanied by extraintestinal manifestations such as an increased risk for atrial fibrillation (AF). Here we will test the hypothesis that during active colitis, dysregulation of parasympathetic signaling increases the propensity for atrial arrhythmic events. Methods: Dextran Sulfate Sodium (DSS: 3%, 7days) treated mice (C57BL/6) exhibit disrupted intestinal barrier function that mimics the disease phenotype of active colitis. Changes in atrial electrophysiology was quantified in-vivo (EKG) and in the Langendorff (LD)-perfused heart (atrial electrograms) during peak inflammation (DSS A ) and remission (DSS R ). Results: During peak inflammation, structural remodeling was reflected in a decreased heart weight to tibia length ratio (Control (CTL A ): 9.9±0.4 mg/mm, n=10; DSS A : 8.8±0.3 mg/mm, n=12; p&lt;0.05) whereas electrophysiological atrial remodeling was supported by a prolonged P-wave duration (CTL A : 25.5±0.6 ms, n=10; DSS A : 31.2±0.6 ms, n=24; p&lt;0.0001) and shortened atrial effective refractory period (CTL A : 27.3±1.7 ms, n=4; DSS A : 19.3±0.6 ms, n=4; p&lt;0.01). In comparison to CTL A , DSS A mice exhibited autonomic dysregulation reflected in an attenuated heart rate (HR) variability and a decreased change in HR in response to the muscarinic receptor blocker atropine (CTL A : 7.6±1.8 %, n=5; DSS A : 2.2±0.7 %, n=7; p&lt;0.01). The decreased vagal tone in DSS A coincided with an exaggerated response to the parasympathomimetic carbachol (CCh, 150ng/g) that resulted in a larger decrease in HR (in vivo: CTL A : -12.3±3.1 %, n=10; DSS A : -46.0±5.6 %, n=10; p&lt;0.0001) and increased number of spontaneous arrhythmic events (CTL A : 1.7±0.6 events/min, n=10; DSS A : 9.8±3.8 events/min, n=10; p&lt;0.05) in vivo and in the LD-configuration. The susceptibility for pacing induced AF trended to be increased in DSS A animals. Structural and electrophysiological changes were reversible upon remission. Conclusion: Active colitis induces transient structural and electrophysiological remodeling. We propose that dysregulation of cholinergic signaling drives the increased propensity for atrial arrhythmia.
Abstract P1018: Bone Marrow Progenitor Cell-Derived Exosomes Activate Cardiac Fibroblasts Via Mir-21a-5p Mediated Integrin Alpha V Stabilization
Authors: Prabhat Ranjan, Roshan Kumar Dutta, Qinkun Zhang, Prasanna Krishnamurthy, Hind Lal, Gangjian Qin, Suresh Verma
Journal: Circulation Research (2022)

Abstract: Heart failure is leading cause of death worldwide, and cardiac fibrosis is the hallmark of heart failure. We previously showed that interleukin-10 (IL10) treatment significantly reduces pressure overload-induced cardiac fibrosis. We also have demonstrated that fibroblast progenitor cells (bone marrow-prominin positive cells; FPCs) play a prominent role in developing cardiac fibrosis, yet the mechanism is largely unknown. Here, we hypothesized that pro-fibrotic miRNAs enriched in exosomes derived from IL10 KO FPCs promote fibroblast activation and cardiac fibrosis in pressure-overloaded myocardium. Methods: Exosomes were isolated from WT and IL-10KO FPCs. Exosomal miRNAs profiling was performed using fibrosis-associated miRNA profiler kit from Qiagen. To determine the contribution of exosomal miR21 on TAC-induced fibrosis, miR21 level was reduced in FPCs-derived exosomes using miR21 silencer. Modified exosomes were injected into heart immediately after TAC surgery. Results: FPCs were identified as CD45+/prominin-1 cells using FACS. TGFβ treatment exacerbated fibrotic genes (Col1α, fibronectin, periostin, and αSMA) expression in IL10KO FPCs compared to WT-FPCs. Pathway-based miRNA array revealed that IL10KO FPCs exosomes are enriched with miR-21a-5p and facilitated fibroblasts activation as observed by qPCR (αSMA and Col1α), western (Col1α and TGFβ levels), wound healing, and immunostaining assay (Col1α/DAPI expression) as compared to WT control. Interestingly, miR21 inhibition in IL10KO FPCs exosome using antimiR 21, reduced TGFβ-induced cardiac fibroblast activation. Target prediction database analysis revealed that Integrin Subunit Alpha V (ITGAV) is a strong regulatory target for miRNA21. At molecular level, we found that exosomal miR-21a-5p stabilizes ITGAV, which ultimately enhances fibroblast activation and cardiac fibrosis both in vitro and in vivo. Conclusions: In conclusion, we report that FPCs derived miR21 packaged in exosomes activates cardiac fibroblasts in IL10-KO mice via miR-21a-5p/ITGAV/Col1α signaling axis and increased cardiac fibrosis. IL10 treatment significantly reduced miR21 exosomal packaging, inhibited fibroblasts activation, and reduced cardiac fibrosis following TAC.
Workforce, airborne transmission, and wilful neglect
Authors: Kamran Abbasi
Journal: BMJ (2022)

<h3>Objective</h3> To investigate the aetiology, subsequent preventive strategies and outcomes of stroke despite anticoagulation in patients with atrial fibrillation (AF). <h3>Methods</h3> We analysed consecutive patients with AF with an index imaging-proven ischaemic stroke despite vitamin K-antagonist (VKA) or direct oral anticoagulant (DOAC) treatment across 11 stroke centres. We classified stroke aetiology as: (i) competing stroke mechanism other than AF-related cardioembolism; (ii) insufficient anticoagulation (non-adherence or low anticoagulant activity measured with drug-specific assays); or, (iii) AF-related cardioembolism despite sufficient anticoagulation. We investigated subsequent preventive strategies with regard to the primary (composite of recurrent ischaemic stroke, intracranial haemorrhage, death) and secondary endpoint (recurrent ischaemic stroke) within 3 months after index stroke. <h3>Results</h3> Among 2946 patients (median age 81 years; 48% women; 43% VKA, 57% DOAC), stroke aetiology was competing mechanism in 713 patients (24%), insufficient anticoagulation in 934 (32%) and cardioembolism despite sufficient anticoagulation in 1299 (44%). We found high rates of the primary (27% of patients; completeness 91.6%) and secondary endpoint (4.6%; completeness 88.5%). Only DOAC (vs VKA) treatment after index stroke showed lower odds for both endpoints (primary: adjusted OR (aOR) (95% CI) 0.49 (0.32 to 0.73); secondary: 0.44 (0.24 to 0.80)), but not switching between different DOAC types. Adding antiplatelets showed higher odds for both endpoints (primary: aOR (95% CI) 1.99 (1.25 to 3.15); secondary: 2.66 (1.40 to 5.04)). Only few patients (1%) received left atrial appendage occlusion as additional preventive strategy. <h3>Conclusions</h3> Stroke despite anticoagulation comprises heterogeneous aetiologies and cardioembolism despite sufficient anticoagulation is most common. While DOAC were associated with better outcomes than VKA, adding antiplatelets was linked to worse outcomes in these high-risk patients. Our findings indicate that individualised and novel preventive strategies beyond the currently available anticoagulants are needed. <h3>Trial registration number</h3> ISRCTN48292829.
Abstract P3105: Improving Cardiovascular Toxicity Of Chronic Myeloid Leukemia Therapy.
Authors: Anna Hnatiuk Hnatiuk, Arne Bruyneel, Dhanir Taylor, Mallesh Pandrala, Ricardo Serrano, Dries Feyen, Yusuke Nakauchi, Michelle Vu, Prashila Amatya, Ravindra Majeti, Sanjay Malhotra, Mark Mercola
Journal: Circulation Research (2022)

Introduction: Ponatinib is one of the most cardiotoxic Tyrosine Kinase Inhibitors (TKIs), but continues to be used in clinical practice as it is the only TKI effective against the most common ABL T315I mutation in Chronic Myeloid Leukemia (CML). Long-term exposure to ponatinib increases cardiovascular events including myocardial infarction, heart failure, stroke, peripheral vascular disease and venous thrombosis. Novel therapeutics are needed to provide treatment for this common form of CML while avoiding cardiovascular side effects. Hypothesis: Chemical reengineering can create novel TKIs effective against T315I mutant CML but with reduced cardiovascular toxicity. Methods: Using fragment-based approach, we generated new, safer analogues of ponatinib. The anti-tumor efficacy of these analogues was tested in 2 different CML cell lines (K562 T315I and KCL22 T315I) and in CML patient samples. We assayed for myocardial toxicity by measuring contractile function in human iPSC-cardiomyocytes (hiPSC-CMs) using high-throughput functional imaging, and assayed for vascular toxicity by measuring vasculogenesis in human microvascular endothelial cells (HMVECs). Finally, we confirmed the safer cardiovascular profile and adequate anti-tumor efficacy in an in vivo xenograft mouse model of CML. Results: The new analogues inhibited T315I BCR-ABL kinase activity similar to ponatinib and suppressed T315I mutant CML tumor growth in vitro and in vivo . Compared to ponatinib, the new compounds showed markedly decreased adverse effects on contractility of hiPSC-CMs and vasculogenesis in HMVECs in vitro . The therapeutic window was increased in vivo , leading to regression of human T315I mutant CML xenografts comparable to ponatinib but without increased levels of cardiac troponin. Additionally, we identified multiple kinases, including FGFR1, that were inhibited by ponatinib but not the analogues, suggesting that there is a specific set of kinases responsible for ponatinib toxicity. Conclusions: This study demonstrates that chemical reengineering can generate novel, cardiovascular-safe TKIs that retain effective therapeutic properties against CML carrying ABL T315I mutation, but that exhibit minimal cardiovascular toxicity compared to ponatinib.
Abstract GS108: Troponin I Tyrosine-26 Phosphorylation Improves Relaxation And Is Beneficial During Pathological Diastolic Dysfunction
Authors: Lorien Salyer, Sarah Sturgill, Elizabeth Brundage, Hussam Salhi, Vikram Shettigar, Eaman Abay, Mark T Ziolo, Brandon Biesiadecki
Journal: Circulation Research (2022)

Diastolic dysfunction contributes to disease in both heart failure with preserved and reduced ejection fraction. There are currently no approved therapies to accelerate impaired relaxation for heart failure patients with diastolic dysfunction. A healthy heart can modify its ability to relax through post-translational modifications (e.g., phosphorylation) of myofilament proteins. The inhibitory subunit of the troponin complex, troponin I (TnI), is a key regulator of cardiac contraction and relaxation and is endogenously phosphorylated at Tyr-26. We previously demonstrated that this novel tyrosine phosphorylation decreases calcium sensitivity and accelerates calcium dissociation from troponin C. We therefore hypothesize that increasing TnI Tyr-26 phosphorylation will accelerate relaxation and be beneficial during pathological diastolic dysfunction. To determine the effects of TnI Tyr-26 phosphorylation in vivo , we generated a phospho-mimetic mouse with TnI Tyr-26 mutated to Glu. Structural and functional echocardiography and hemodynamics measurements demonstrate that TnI Tyr-26 phosphorylation accelerates relaxation and increases diastolic function in vivo . To determine the effect of this TnI Tyr-26 phosphorylation mediated acceleration of diastolic function during disease, we performed unilateral nephrectomy with DOCA-salt (neph/DOCA) to induce diastolic dysfunction. Wild-type mice subjected to neph/DOCA develop left ventricular hypertrophy, enlarged left atria, elevated diastolic pressure, and slowed relaxation, indicative of diastolic dysfunction. In contrast with wild-type, TnI Tyr-26 phosphorylation mice subjected to neph/DOCA display normal diastolic function without any cardiac remodeling. Overall, we demonstrate that TnI Tyr-26 phosphorylation inhibits the development of diastolic dysfunction and is therefore a novel mechanism to accelerate myocardial relaxation in vivo.
Abstract P1091: Granulocyte-Macrophage Colony-Stimulating Factor Signaling Pathway And Antiarrhythmic Effect Of Renal Denervation In Chronic Heart Failure
Authors: Wenfeng Hu, Huiyin Tu, Michael Wadman, Yulong Li, Dongze Zhang
Journal: Circulation Research (2022)

Renal denervation (RDN) is widely investigated in multiple studies of sympathetically driven cardiovascular diseases. While the therapeutic potential of RDN for ventricular arrhythmia has been reported, the mechanisms responsible for the antiarrhythmic effect of RDN are poorly understood. Our recent study showed that macrophage expansion-induced neuroinflammation in the stellate ganglion (SG) was a critical factor for cardiac sympathetic overactivation and ventricular arrhythmogenesis in chronic heart failure (CHF). This study aims to investigate if and how RDN decreases ventricular arrhythmias through attenuating neuroinflammation in cardiac sympathetic postganglionic (CSP) neurons in CHF. CHF was induced by acute surgical ligation of the left coronary artery in rats. Completed bilateral RDN was achieved by surgically cutting all the visible renal nerves around the renal artery and vein and followed by application of 70% ethanol around the vessels. Using immunofluorescence staining and Western blot analysis, we found that expression of granulocyte-macrophage colony-stimulating factor receptor-α subunit (GM-CSFRα), and Iba1 (an activated macrophage marker) in macrophages from the SG were increased in 16-week CHF rats, compared with age matched sham rats. In the ELISA experiment, we observed high levels of GM-CSF in kidney, serum, and SG in CHF rats, which were markedly reduced at 3 weeks after RDN. CHF-elevated macrophage activation and expression of GM-CSFRα in the SG were decreased by RDN. Flow cytometry data confirmed that CHF-increased percentage of macrophages in the SG was reduced at 3 weeks after RDN. Patch-clamp data found that RDN reduced the N-type Ca 2+ currents in CSP neurons from CHF rats (50.5+3.3 pA/pF in CHF rats vs. 28.6+2.2 pA/pF in CHF+RDN rats, P&lt;0.05). RDN attenuated CHF-enhanced cardiac sympathetic nerve activity. ECG data from 24-hour continuous telemetry recording in conscious rats revealed that RDN decreased the incidence and duration of spontaneous ventricular tachyarrhythmias in CHF rats. Based on these data, we confirm that RDN inhibits cardiac sympathetic overactivation and ventricular arrhythmogenesis through GM-CSF-macrophage activation-neuroinflammation-N-type Ca 2+ channel signaling axis in CHF.
Autologous bone marrow versus non‐mobilized peripheral blood stem cell transplantation for lymphoid malignancies: A prospective, comparative trial
Authors: Daniel J. Weisdorf, Catherine M. Verfaillie, Wesley J. Miller, Bruce R. Blazar, Elizabeth Perry, Xiao Ou Shu, Kathleen Daniels, Peter Hannan, Norma K.C. Ramsay, John H. Kersey, Philip B. McGlave
Journal: American Journal of Hematology (1997)
Abstract P1026: Creg1 Inhibits Cardiomyocyte Proliferation And Promotes Myocardial Differentiation And Compaction During Postnatal Cardiac Development
Authors: NaYoung Yang, Yanmei Qi, Joshua Chao, Leonard Lee, Shaohua Li
Journal: Circulation Research (2022)

Introduction: Overexpression of cellular repressor of E1A-stimulated genes 1 (CREG1) promotes the formation of compact, contracting myocardium-like structures during cardiomyogenesis from embryonic stem cells. Cell biology studies suggest that CREG1 promotes differentiation and inhibits proliferation of developing cardiomyocytes. This study aims to understand the role of CREG1 during myocardial development in vivo . Methods: Cardiac tissues were harvested from wild-type (WT) and constitutive Creg1 knockout (KO) postnatal day 1.5 and 17 through timed mating of heterozygous Creg1 mice. Creg1 KO mice were compared with Creg1 WT littermates using immunoblotting, immunofluorescence, and methylene blue staining. Results: Postnatal day 1.5 Creg1 KO hearts showed lower levels of expression of slow skeletal muscle troponin I (TnI) compared with WT counterparts. No significant difference in expression was seen between WT and KO Creg1 hearts for myosin light chain 3 (MLC3), myosin heavy chain (MHC), and cardiac troponin I. Immunofluorescence staining revealed increased numbers of PCNA (Proliferating Cell Nuclear Antigen) positive nuclei in postnatal day 1.5 Creg1 KO hearts, suggesting enhanced cardiomyocyte proliferation after loss of CREG1. Methylene blue staining in postnatal day 17 hearts displayed decreased myocardial compaction in Creg1 KO mice. Conclusion: CREG1 may promote cardiomyocyte differentiation and inhibit proliferation during postnatal myocardial development. Ablation of CREG1 results in cardiac compaction defects. Our findings suggest an important role for CREG1 in cardiac development.
Abstract P2024: Novel Inhibitor Of P38 Mitogen-activated Protein Kinase Reverses Hypoxia-induced Pulmonary Hypertension In Rats
Authors: Grazielle F Silva, Jaqueline S Da Silva, Marina Silva, Tadeu Montagnoli, Allan K Alencar, Bruna Rocha, Rosana Freitas, Carlos Fraga, Gisele Zapata-Sudo
Journal: Circulation Research (2022)

Pulmonary arterial hypertension (PAH) is a disease characterized by pulmonary vascular changes with subsequent right ventricular (RV) failure. This work investigated the hypothesis that a new p38-alpha mitogen-activated protein kinase (p38-alpha MAPK) inhibitor, named LASSBio-1824, could interfere on PH model in rats. Methods: HP was induced in male Wistar rats through the exposure to hypoxia (10% O2) during 3 weeks, in combination to i.p. injection of an antagonist of vascular endothelial growth factor receptor (SU5416; 20 mg/kg/weekly). Control rats were kept in normoxia. After 3 weeks, echocardiography images confirmed PH using the pulmonary artery (PA) outflow waveform. After disease onset, animals were randomly divided into three groups: control + vehicle (DMSO), PH + vehicle and PH + LASSBio-1824 (50 mg/kg/day), in which vehicle and LASSBio-1824 were orally administered (gavage) during two weeks. All experiments were in accordance with the Animal Care and Use Committee at Federal University of Rio de Janeiro (039/19). Results: Pulmonary acceleration time (PAT; ms) was reduced from 40.0 ± 2.1 (control) to 24.2 ± 1.8 in PH + vehicle group (p &lt; 0.05) and restored to 36.8 ± 2.9 after treatment with LASSBio-1824 (p &lt; 0.05). RV afterload was detected in PH group because of the increase of systolic pressure (mmHg) from 23.2 ± 1.5 (control) to 46.7 ± 2.8 (p &lt; 0.05) which was reduced to 19.4 ± 2.7 with LASSBio1824 treatment. Medial wall thickness (%) of distal pulmonary arteries (PA, &lt; 50 μm) was evaluated by using immunohistochemistry for alpha smooth muscle actin (alpha-SMA) which was increased from 64.0 ± 4.9 (control) to 80.8 ± 2.7 in PH group (p &lt; 0.05), but it was significantly reduced to 55.0 ± 1.3 after treatment with the inhibitor (p &lt; 0.05). Acetylcholine (ACh)-induced maximal relaxation (%) of PA from normal and PH rats, was reduced from 67.5 ± 1.6 to 51.9 ± 4.9 (p &lt; 0.05). Therefore, the treatment with the p38 inhibitor normalized vascular reactivity to 73.0 ± 3.3 %. The immunohistochemistry for c-fos protein, a product of the p38 pathway related to cell proliferation, showed an increase of stained myocyte nuclei (%) in PH animals of 36.5 ± 1.5 when compared to normal group of 20.2 ± 4.2. The inhibitor significantly reduced ratio to 24.0 ± 2.3% (p &lt; 0.05). PH increased the inflammatory condition because the expression of inducible nitric oxide synthase altered from 10.4 ± 1.9% (control) to 31.9 ± 2.2% and it was recovered by the inhibitor to 15.5 ± 2.2% (p &lt; 0.05). In conclusion, the new p38-alpha MAPK inhibitor represents an important approach for the future treatment of PH, since it improves the underlying remodeling and inflammation processes.
Abstract P1074: High-fat High-sugar Diet Promotes Expression Of The Stress Response Protein REDD1 In Cardiomyocytes By Activation Of A PERK/ATF4 Signaling Axis
Authors: Shaunaci A Stevens, Allyson L Toro, Jessica M Pfleger, Elisa A Bradley, Michael D Dennis
Journal: Circulation Research (2022)

Obesity and type 2 diabetes represent a surging public health crisis, impacting nearly half of American adults. Heart failure is a leading cause of mortality and morbidity in patients with diabetes and obesity. Much remains unknown regarding the molecular players that contribute to heart failure, but at the cellular level ER stress and inflammation are considered key hallmarks of cardiomyocyte dysfunction. The stress response protein regulated in development and DNA damage 1 (REDD1) is upregulated as a consequence of ER stress in multiple pathological conditions and was recently shown to promote inflammatory signaling. However, a role for diabetes-induced REDD1 in the context of heart failure has yet to be explored. Herein, we investigated the hypothesis that consumption of a pro-diabetogenic diet enhances REDD1 expression in cardiomyocytes by promoting ER stress. C57BL6/N mice were fed either a control chow or a high-fat high-sugar (HFHS, 42% kcal fat, 34% sucrose by weight) diet for 12 weeks. Mice fed a HFHS diet developed obesity and glucose intolerance. Hearts of mice fed a HFHS diet had an abundance of REDD1 mRNA and exhibited an increase in ER stress and inflammation characterized by phosphorylation of the ER kinase PERK, XBP-1 splicing, and IL-1β expression. We found that exposing both rat H9c2 and human AC16 cardiomyocytes to the saturated fatty acid palmitate and/or hyperglycemic conditions enhanced REDD1 mRNA and protein expression concomitant with an increase in markers of ER stress. PERK inhibition was sufficient to prevent the increase in REDD1 mRNA expression in cardiomyocytes exposed to hyperlipidemic conditions. Similarly, the transcription factor ATF4 was required for the increase in REDD1 mRNA and protein in cells exposed to hyperlipidemic conditions. We also found that REDD1 deletion was sufficient to reduce pro-inflammatory cytokine expression in human cardiomyocytes exposed to hyperglycemic and hyperlipidemic conditions. Overall, the findings provide evidence that HFHS environments contribute to the development of inflammation in cardiomyocytes by promoting REDD1 expression via activation of a PERK/ATF4 signaling axis.